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REVIEW ARTICLE
GUT Microbiome-GUT Dysbiosis-Arterial Hypertension: New Horizons Vasiliki Katsi1, Matthaios Didagelos2,*, Stamatios Skevofilax3, Iakovos Armenis3, Athanasios Kartalis3, Charalambos Vlachopoulos1, Haralambos Karvounis2 and Dimitrios Tousoulis1 1 st
1 Cardiology Department, Hippokration General Hospital, National and Kapodistrian University of Athens, Athens, Greece; 21st Cardiology Department, AHEPA General Hospital, Aristotle University of Thessaloniki, Greece; 3 Cardiology Department, Skylitseio General Hospital, Chios, Greece
ARTICLE HISTORY Received: November 15, 2017 Revised: June 07, 2018 Accepted: June 08, 2018 DOI: 10.2174/1573402114666180613080439
Abstract: Arterial hypertension is a progressive cardiovascular syndrome arising from complex and interrelated etiologies. The human microbiome refers to the community of microorganisms that live in or on the human body. They influence human physiology by interfering in several processes such as providing nutrients and vitamins in Phase I and Phase II drug metabolism. The human gut microbiota is represented mainly by Firmicutes and Bacteroidetes and to a lesser degree by Actinobacteria and Proteobacteria, with each individual harbouring at least 160 such species. Gut microbiota contributes to blood pressure homeostasis and the pathogenesis of arterial hypertension through production, modification, and degradation of a variety of microbial-derived bioactive metabolites. Animal studies and to a lesser degree human research has unmasked relative mechanisms, mainly through the effect of certain microbiome metabolites and their receptors, outlining this relationship. Interventions to utilize these pathways, with probiotics, prebiotics, antibiotics and fecal microbiome transplantation have shown promising results. Personalized microbiome-based disease prediction and treatment responsiveness seem futuristic. Undoubtedly, a long way of experimental and clinical research should be pursued to elucidate this novel, intriguing and very promising horizon.
Keywords: Gut microbiome, gut flora, microorganisms, arterial hypertension, short chain fatty acids, probiotics, prebiotics. 1. INTRODUCTION Gut microbiota or simply gut flora is a generalized term for an array of microorganisms that live in the digestive tract. While these microorganisms have a primordial role in human metabolism, it is not a surprise that their non-harmful coexistence gives rise to a mutualistic relationship between the human macroorganism and the largest population of life in this human niche. Recently, much research has focused on gut microbiota and their interaction with human disease. Arterial hypertension, a major contributor to cardiovascular disease and death is a multifactorial medical condition in which the blood pressure (BP) in the systemic circuit is persistently elevated. Nearly 1 in every 3 American adults, approximately 70 million people suffer from chronically elevated blood pressure. It is estimated that in 2013 more than 360,000 deaths were attributed to hypertension [1-3]. Much research has been compiled regarding hypertension; however, just recently attention has been veered towards gut microbiota and its relation to hypertension. This review deals *Address correspondence to this author at the 1st Cardiology Department, AHEPA General Hospital, Aristotle University of Thessaloniki, Greece, St. Kyriakidi 1, P.C.: 54636, Thessaloniki, Greece; Tel: +306942488823; Fax: +302310994837; E-mail:
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with the interactions of gut microbiota and their role in arterial hypertension. 2. ARTERIAL HYPERTENSION 2.1. Definition and Epidemiology Arterial hypertension is a progressive cardiovascular syndrome arising from complex and interrelated etiologies [4]. This is usually defined according to persistently elevated blood pressure measurements; more specifically, a systolic BP of ≥140 mmHg and/or diastolic BP ≥90 mmHg is considered as a hypertensive state [5]. It is divided into primary or “essential” hypertension (95% of cases) where no clear identifiable cause can be found and secondary hypertension (remaining 5% of cases) when it is caused by a specific renal or adrenal disease [6]. Early signs of the syndrome frequently present before BP elevation is sustained, limiting the pragmatic reality of a simple BP threshold definition [4]. Nonetheless, the usefulness of such definitions allows for the practical management of hypertension [5, 7, 8]. The prevalence of arterial hypertension is very high amongst adults worldwide. It is estimated that one-fifth of adults are hypertensive. Moreover, the frequency of hypertension among adults increases as age increases, reaching nearly fifty percent in people older than 60 years [2]. This chronic elevation © 2018 Bentham Science Publishers
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Fig. (1). The interaction between the gut microbiome and arterial hypertension.
of blood pressure over time causes end-organ damage and results in increased morbidity and mortality [9]. 2.2. Pathophysiology of Arterial Hypertension The pathophysiology of arterial hypertension is complex and multi-etiological. Although there is no single identifiable cause of essential hypertension, the factors modulating systemic blood pressure are well known and regulated by renal, genetic, environmental and endocrine interactions. They include the cardiac output and peripheral vascular resistance, renin-angiotensin-aldosterone system, autonomic nervous system, sodium and water retention, endothelial dysfunction, vasoactive substances, hypercoagulability, insulin sensitivity, intrauterine influences, genetic factors, immune system and inflammation (Fig. 1) [6, 9-12]. 2.2.1. Cardiac Output and Peripheral Vascular Resistance Blood pressure results from the balance between cardiac output (defined by stroke volume and heart rate) and peripheral vascular resistance (depended on vascular tone and vascular structure). Increased cardiac output resulting from sympathetic dysfunction is thought to be the first step for the development of early hypertension and then a gradual increase in peripheral resistance tries to maintain homeostasis resulting in increased vascular stiffness in later stages of hypertension. 2.2.2. Renin-angiotensin-aldosterone System It is the most important of the endocrine systems regulating blood pressure causing vasoconstriction, sodium and water retention. It is stimulated by the sympathetic nervous system (renin release is stimulated by β- and decreased by αadrenoceptor stimulation) and glomerular hypoperfusion. Important noncirculating “local” reninangiotensin epicrine or paracrine systems have also been reported to affect blood pressure. 2.2.3. Autonomic Nervous System The autonomic nervous system regulates blood pressure causing both arteriolar constriction and arteriolar dilatation
in response to stress and physical exercise. It affects also the cardiac output and renin release. In hypertension, both increased release of, and enhanced peripheral sensitivity to, norepinephrine can be found combined with a resetting of the baroreflexes and decreased baroreceptor sensitivity. 2.2.4. Sodium and Water Retention It results either from the action of other endogenous systems or from dietary habits. Sodium, via the sodium-calcium exchange mechanism, causes an increase in intracellular calcium in vascular smooth muscle cells resulting in increased vascular tone. Reduced renal blood flow, reduced nephron mass, and increased angiotensin levels or mineralocorticoids are the primary causes for this abnormal relationship. Saltsensitivity (a change in blood pressure >5-10% as a result of a change in NaCl intake) is associated with increased cardiovascular risk even if blood pressure does not transcend hypertensive limits. A low-sodium diet is traditionally considered as part of a healthy lifestyle and an antihypertensive regimen. Notably, there is also the phenomenon of reverse salt-sensitivity where low-sodium diet can surprisingly increase blood pressure, pointing out that there are unknown pathways of salt-sensitive and salt-resistant genes to be discovered. 2.2.5. Endothelial Dysfunction The vascular endothelium produces local vasoactive agents such as nitric oxide (causing vasodilatation) and endothelin (causing vasoconstriction). Although the degree of endothelial dysfunction is directly correlated with the severity of hypertension, however, it is not clear which component predominates. Once hypertension is established, the altered endothelial function does not subside even with effective anti-hypertensive treatment. In addition to nitric oxide, other vasorelaxing factors (arachidonic acid metabolites, reactive oxygen species, vasoactive peptides and microparticles of endothelial origin) affect vascular tone and may contribute to excessive vascular oxidative stress and vascular inflammation. Moreover, the endothelial progenitor cells (precursors of the mature endothelial cells) are implicated in
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the maintenance of arterial stiffness and are now considered as determinants of endothelial function. 2.2.6. Vasoactive Substances There are many molecules that affect vascular tone and sodium transport regulating blood pressure control. Bradykinin (belongs to the kallikrein-kinin system) is a potent vasodilator, with autocrine and paracrine action, stimulates the release of other vasoactive substances like prostaglandins and is inactivated naturally by the angiotensin-converting enzyme. Nitric oxide is produced by arterial and venous endothelium and causes vasodilatation. Atrial natriuretic peptide is secreted from the atria of the heart, mediates its functions by membrane-bound guanylate cyclase linked receptor (NPR-A), which further activates intracellular cGMP mediated processes and results in increased sodium and water excretion from the kidney. Endothelin is a powerful vasoconstrictor, producing a salt-sensitive increase in blood pressure and activating local renin-angiotensin systems. Adrenal steroids also increase blood pressure by sodium and water retention (mineralocorticoids) or increased vascular reactivity (glucocorticoids). Ouabain, a naturally occurring steroidlike substance, interferes with cell sodium and calcium transport causing also vasoconstriction. 2.2.7. Hypercoagulability
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of it. Thus, essential hypertension is believed to turn up as a genetic predisposition intermingled with various lifestyle factors that affect their phenotypic expression. Up to now more than 25 rare mutations and 53 SNPs have been described in the genetic background of hypertension. Some of them, like the SNPs in the uromodulin gene (UMOD), the nitric oxide synthase gene (eNOS) and the atrial and brain natiuretic peptides genes (NPPA/B) have been linked to a specific pathophysiologic pathway and could be possible targets for future drug development, whereas the majority of SNPs await for their role to be elucidated. 2.2.11. Immune System and Inflammation Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase by generating superoxide and other reactive oxygen species play a major role in many forms of hypertension. Renal proteins that have been oxidatively modified by γketoaldehydes (isoketals) stimulate dendritic cells to produce interleukin-6, -1β, and -23 as well as costimulatory proteins CD80 and CD86 that then cause T cell proliferation, interferon-γ, and interleukin-17A production and hypertension. This “communication” between the sympathetic nervous system, the immune cells, and cytokine production results finally in vascular and renal dysfunction, leading to the augmentation of hypertension.
This includes the metabolic syndrome, where a summation of risk factors such as obesity, glucose intolerance, diabetes mellitus, hyperlipidaemia share a common pathway to finally cause hypertension and vascular damage.
Over the spectrum of the disease, essential hypertension progresses from intermittent hypertension to established hypertension. Target organ damage is found at the far side of the spectrum whereas a long invariable asymptomatic period is found in the beginning. Generally speaking, essential hypertension may begin at a young age of up to 30 years old by an increased output mechanism and then progresses to early hypertension in people aged up to 40 years of age, where increased peripheral resistance dominates. Established hypertension is observed in persons aged between 30-50 years. At the end of the spectrum is complicated hypertension, in which target organ damage to the aorta, small arteries and vital organs such as the heart kidneys, retina, and central nervous system are evident.
2.2.9. Intrauterine Influences
3. THE HUMAN GUT MICROBIOME
Low birth weight and maternal hypertension in pregnancy have been associated with the development of hypertension and insulin resistance later in life, although definite correlations are difficult to derive.
3.1. Definition
Hypertension results in a prothrombotic or hypercoagulable state demonstrating abnormalities of vessel wall (endothelial dysfunction or damage), the blood constituents (abnormal levels of haemostatic factors, platelet activation, and fibrinolysis), and blood flow (rheology, viscosity, flow reserve), that is related to target organ damage and long-term prognosis. 2.2.8. Insulin Sensitivity
2.2.10. Genetic Factors Although some specific genetic mutations (mainly in the frame of a certain syndrome) can cause secondary hypertension, the rule is that a complex interplay between multiple genes, following a non-Mendelian mode of inheritance, contributes to the development of essential hypertension. Genome-wide association studies have discovered numerous single nucleotide polymorphisms (SNPs) for blood pressure and hypertension, but connecting them to causal pathways remains challenging. The heritability of blood pressure from family studies varies from 30-50%, however, the collective effect of all the discovered genetic loci can explain only 2%
The human microbiome refers to the community of microorganisms that live in or on the human body. They influence human physiology by interfering in several processes such as providing nutrients and vitamins as well as interacting in Phase I and Phase II drug metabolism. The human gut microbiota (HGM) is represented mainly by Firmicutes and Bacteroidetes and to a lesser degree by Actinobacteria and Proteobacteria, with each individual harboring at least 160 such species. They are continuously adapting to lifestyle modifications, such as diet and exercise and can regulate about 10% of the host’s transcriptome (mainly genes related to immunity, cell proliferation, and metabolism). HGM has been recently linked to the pathophysiology of diabetes, cancer, bowel disorders, liver disease, immune conditions, metabolic syndrome and arterial hypertension (Fig. 1) [1315].
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3.2. Mechanisms of Gut Microbiota and Hypertension Interplay Gut microbiota contributes to blood pressure homeostasis and the pathogenesis of hypertension through production, modification, and degradation of a variety of microbialderived bioactive metabolites, like bile acids, vitamins, amino-acids and mainly short-chain fatty acids (SCFAs), which possess immune-modulating properties. For example bacteria of the Bacteroidetes phylum produce large amounts of the SCFAs acetate and propionate and bacteria of the Firmicutes phylum produce large amounts of butyrate SCFA, respectively. This has been proved by studies in “sterilized” mice where lack of gut bacteria results in absence of SCFAs [16-19]. SCFAs have anti-inflammatory properties, modulate immune signaling through binding with the G-protein receptors and cause vasodilatation in vitro and hypotension in vivo in animals. The first G-protein receptor that seems to mediate these actions is the SCFA olfactory receptor 78 (Olfr78), expressed both in olfactory neurons and in the smooth muscle cells of the kidney vessels. Olfr78 binds acetate and propionate thus mediating glomerular filtration rate and renin release. Experimentally, propionate treatment of normal mice results in blood pressure reduction, while oral antibiotics increase blood pressure in Olfr78-deficient mice [2030]. Two other G-protein receptors, Gpr41 (or FFAR3) and Gpr43 (or FFAR2), are also expressed in kidney vessels and propionate treatment of Gpr41-deficient mice results in blood pressure elevation [19, 31]. The complete pathway of all this microbiome-derived metabolite crosstalk remains obscure and additional molecules and receptors are to be discovered (Fig. 1). 3.3. Animal Studies Animal studies have been the first and until now the main research pillar exploring the associations between gut microbiota and hypertension. 3.3.1. Salt-sensitive Dahl Rats The salt-sensitive (S) and the salt-resistant (R) Dahl rats are genetic models of hypertension and normotension, respectively. A high-salt diet increases blood pressure in the S rats while it has no effect on R rats. A reason for this is the significant different cecal microbiota between the S and R rats. Under basal conditions bacteria of the phylum Bacteroidetes and the family Veillonellaceae (of the phylum Firmicutes) are higher in the S rats compared with the R rats. However, antibiotic administration to S rats leading to microbiome depletion did not alter blood pressure response to salt intake. Moreover, fecal microbiome transplantation from S to R rats did not transfer the hypertensive phenotype into the R rats. When the reverse was attempted, fecal microbiome from R to S rats, the hypertensive response of the S rats was exacerbated, followed by significantly elevated plasma levels of the fatty acids acetate and heptanoate. The altered microbial mixture affected plasma SCFA level and subsequently blood pressure homeostasis [13, 19, 32-35].
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3.3.2. Spontaneously Hypertensive Rats (SHRs) SHRs present with elevated blood pressure and increased response to high salt diet compared to normotensive Wistar Kyoto (WKY) control rats. Fecal microbiome differed significantly between the two: In the SHRs the Firmicutes to Bacteroidetes ratio was 5-fold higher, the Actinobacteria and Bifidobacterium population were reduced, the lactateproducing bacteria Streptococcus and Turicibacter were more as compared to WKY rats where the butyrate-producing bacteria Coprococcus and Pseudobutyrivibrio accumulated more. Moreover, induction of low-grade inflammation was supposed to play a role in the augmented vascular contractility displayed in the SHRs [19, 36, 37]. 3.3.3. Pharmacologically-induced Hypertensive Rats In this model angiotensin II was continuously infused into the rats in order to maintain a hypertensive response compared to their controls. The hypertensive rats had lower amounts of microbial species, an increased Firmicutes/ Bacteroidetes ratio and less acetate-producing and butyrateproducing genera. After 4-week antibiotic treatment with oral minocycline, the hypertensive rats showed a reduction in the Firmicutes/Bacteroidetes ratio and mean arterial pressure and an increase in the acetate-producing to butyrateproducing bacteria ratio [19, 36]. 3.3.4. Obstructive Sleep Apnea-Metabolic Syndrome (OSA Met) Rats Obstructive sleep apnea (OSA) represents a major risk factor for hypertension and is often accompanied by obesity. In this model, OSA met rats were implanted with an endotracheal obstruction device and were fed with a high-fat diet, as to resemble the human condition of OSA combined with obesity/metabolic syndrome and compared with control groups treated with endotracheal obstruction device or highfat diet alone. The OSA met rats developed hypertension that did not appear in either of the control groups. Microbiome analysis showed a reduced relative abundance of three main taxa, Clostridiaceae, Dehalobacterium, and Holdemania in the OSA met rats compared with the control group of highfat diet alone. Fecal microbiome was then transplanted from OSA met rats or from the controlled high-fat diet rats into untreated rats, followed additionally by induction of OSA in recipient rats but under normal diet conditions. Microbiome transplantation from the control rats did not cause hypertension to the recipients in contrast with the recipients of the OSA met rat's microbiome whose blood pressure was elevated. These OSA met microbiome recipients showed an increase in the relative abundance of bacteria from the family Coriobacteriaceae, which contains lactate-producing genera and a 4-fold decrease in the relative abundance of the Eubacterium, known to convert lactate to butyrate. To summarize apnea-induced hypertension is associated with a decrease in butyrate-producing bacteria and an increase in lactateproducing bacteria [19, 38-42]. 3.3.5. Gut Dysbiosis In rat models, hypertension is associated with gut dysbiosis, characterized by decreased SCFAs production, change in
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the Firmicute/Bacteroidetes ratio and decreased bacterial richness [19, 32, 36, 38, 43]. 3.3.6. Microbiome-immune Axis Other microbiome mechanisms that may play a role in hypertension, like its modulatory effect on the immune response have not been sufficiently studied. Interestingly, tolllike receptor (TLRs) activation participates in elevated blood pressure and vascular dysfunction. Research with animal models such as TLR-deficient mice will help in discovering any potential involvement of the microbiome-immune axis in blood pressure homeostasis [19, 44-46]. 3.4. Human Studies Studies in human are still in “swaddling” mode and remaining mainly in observational results and lacking investigation of causative associations and mechanisms of interference between microbiome and hypertension. 3.4.1. Human gut Microbiome Analysis Gut microbiome analysis between hypertensives and normotensives depicted a reduced bacterial richness and altered bacterial compositions in hypertensives, however without further data on specific bacterial composition differences [19,36]. 3.4.2. Human Subgingival Microbiome Analysis Periodontitis-causing bacteria, like Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, were found at increased concentrations in subgingival plaque sampling from patients with elevated blood pressure [19, 47]. 3.5. Gut Microbiota as an Antihypertensive Target Current antihypertensive treatment includes lifestyle interventions like weight loss, physical activity, low sodium diet, controlled alcohol consumption and other nutritional adjustments. All these are usually accompanied by a variety of antihypertensive medications acting at different elements of the arterial hypertension pathophysiologic cascade, being less or more effective and well-tolerated. Targeting the microbiome as a possible antihypertensive regimen appears to be a challenging but exciting road [5, 19, 48, 49]. 3.5.1. Probiotics (Live micro-organisms which, when Administered in Adequate Amounts, Confer a Health Benefit on the Host): Bacteria-fermented Milk Bacteria-fermented milk inhibits angiotensin converting enzyme (ACE) activity by disrupting proteins into hypotensive peptides, as part of their metabolic processes. Studies in vitro and in rats showed that this kind of milk, fermented by Lactobacillus helveticus and Saccharomyces cerevisiae or Lactobacillus paracasei and Lactobacillus Plantarum, managed to lower blood pressure. In human studies, Lactobacillus helveticus-fermented milk for 1-2 months reduced the systolic blood pressure in hypertensives. This also happened with probiotics in the form of yogurt and cheese (Fig. 1) [19, 50-59].
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3.5.2. Prebiotics (Substances that Induce the Growth or Activity of Microorganisms that Contribute to the Wellbeing of their Host): β-glucan In a human study, high molecular weight β-glucan (found in oat and barley) consumption altered gut microbiota composition, by increasing Bacteroidetes (genus Bacteroides) and decreasing Firmicutes (genus Dorea) and lowered blood pressure (Fig. 1) [19, 60-63]. 4. HUMAN GUT MICROBIOTA - A FINGERPRINT OF PERSONALIZED MEDICINE? HGM is unique to each individual, which inadvertently is involved in disease expression, prognosis and treatment modalities. HGM probably creates a predisposition to multiple disorders such as obesity, type I diabetes mellitus, colorectal, cancer and inflammatory bowel disease. Moreover, HGM interferes with drugs, like the chemotherapeutic agent irinotecan, the cardiac glycoside digoxin, the antidiabetic metformin, the hypolipidemic simvastatin, by chemically modifying, metabolizing or affecting their bioavailability. Thus, the individual responsiveness and subsequent effectiveness and/ or safety of treatment may vary significantly. However, no data still exists for possible interactions of HGM with antihypertensive medical treatment, although this could explain the variable drug resistance in the disease [19, 64-71]. CONCLUSION The association between gut microbiota and hypertension has only begun to emerge. Animal studies and to a lesser degree human research has unmasked relative mechanisms, mainly through the effect of certain microbiome metabolites and their receptors, outlining this relationship. Interventions to affect these pathways, with probiotics, prebiotics, antibiotics and fecal microbiome transplantation have shown promising results. Personalized microbiome-based disease prediction and treatment responsiveness seem futuristic. Undoubtedly, a long way of experimental and clinical research has to be pursued to elucidate this novel, intriguing and much promising horizon. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENTS Declared none. REFERENCES [1] [2] [3]
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